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Understanding DNA Damage Response and DNA Repair in Multiple Myeloma
Cole Petrilla1, Joshua Galloway1, Ruchi Kudalkar1
1Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Abstract:
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.
Insights
Multiple myeloma involves genetic changes affecting DNA damage response (DDR) and repair. These alterations promote cancer growth and treatment resistance, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multiple myeloma (MM) is a plasma cell cancer marked by genetic alterations.
- Aberrant DNA damage response (DDR) and repair pathways are crucial for MM development and therapy resistance.
Purpose of the Study:
- To review DDR and DNA repair mechanisms in normal tissues.
- To explore the role of these pathways in MM progression and phenotypes.
- To identify potential therapeutic strategies targeting DDR and repair in MM.
Main Methods:
- Literature review of DNA damage response (DDR) and repair mechanisms.
- Analysis of genetic abnormalities in multiple myeloma (MM).
- Discussion of therapeutic implications of DDR and repair pathways.
Main Results:
- MM exhibits altered DDR and repair, facilitating tumor survival and treatment resistance.
- Defects in apoptosis pathways (e.g., ATM, TP53, TP73) contribute to MM progression.
- Therapeutic agents like melphalan and bortezomib induce DNA damage in MM.
Conclusions:
- Understanding DDR and DNA repair in MM is critical for developing novel therapies.
- Targeting these pathways presents a promising strategy for overcoming MM treatment resistance.
- Further research into DDR and repair mechanisms could lead to improved MM patient outcomes.
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